INFLAMMATORY DISORDERS OF THE SKIN AND SUBCUTIS:
A PRACTICAL AND ANALYTICAL APPROACH
CASE #3: PSORIASIS
Cynthia M. Magro, M.D., A.Neil Crowson, M.D., and Martin C. Mihm Jr., M.D.
Psoriasis is an idiopathic hyperproliferative state of the epidermis which produces a chronic inflammatory
skin disorder which affects one to two percent of the population can be broadly categorized into specific
subtypes, namely; 1) psoriasis vulgaris, 2) generalized pustular psoriasis, 3) localized pustular psoriasis,
4) psoriasis associated with a erythroderma, 5) psoriasis associated hypersensitivity reactions, and 6)
psoriasis associated with HIV infection.
The lesions are pink to red papules and plaques which typically involve the scalp, sacral region and the
extensor surfaces of the extremities and are covered with fine silvery scales which bleed when scraped, to
yield the Auspitz sign. When the flexural aspects of the extremities, intertriginous areas, and genitilia
are involved, the term inverse psoriasis is applied. Oral lesions refered to as geographic
stomatitis/mucositis can be seen in some patients. Psoriatic arthritis, classically observed in psoriasis
vulgaris, may also be seen in other variants. It afflicts the interphalangeal joints, although a
symmetrical large joint arthritis indistinguishable from rheumatoid arthritis may also be seen. Regarding
generalized pustular psoriasis, there are three forms; 1) acute generalized pustular psoriasis of von
Zumbusch , 2) generalized pustular psoriasis of pregnancy (impetigo heptaformis), and 3) infantile or
juvenile pustular psoriasis. The lesions clinically comprise sterile pustules on an erythematous scaly base
accompanied by severe constitutional symptoms.
Localized pustular psoriasis, classically presents as pustules confined to the palms and soles, the term
pustolosis palmaris et plantaris has been used. In psoriasis associated with HIV infection, extensive
erythroderma is the rule. Palmo-plantar involvement, inverse psoriasis and psoriatic arthritis are more
frequent in patients who develop psoriasis in the setting of HIV infection.
In psoriasis vulgaris, there is a distinctive pattern of epidermal hyperplasia characterized by regularly
elongated rete with variable rete fusion.
There is diminution of the granular cell layer with areas of
complete granular cell layer absence. The stratum corneum is markedly thickened with both parakeratosis,
orthohyperkeratosis, and plasma admixed with neutrophils. There may be architectural disarray and
dysmaturation of the epidermis and suparbasilar mitoses are frequent. Striking alterations of the dermal
papillae capillaries are observed; capillaries appear increased in number and are dilated, lying in intimate
apposition to the cytoplasmic membranes of the basilar keratinocytes. Attenuation of the suprapapillary
plates is frequent. Inflammation is a ubiquitous feature of the psoriatic plaque. The infiltrate is
located both within the superficial dermis and in the epidermis. The superficial dermal infiltrate is of
maximum intensity within the dermal papillae and is composed almost exclusively of lymphocytes with a minor
neutrophilic population. There is exocytosis of inflammatory cells into the epidermis, localized mainly to
the suprapapillary plates. The initial infiltrating cell is a lymphocyte, followed by an influx of
neutrophils into the epidermis and stratum corneum. Permeation of widened keratinocytic spaces of the more
superficial layers of the epidermis by neutrophils is referred to as spongiform pustulation of Kogoj.
Intracorneal and subcorneal micro-abscesses referred to as Munro micro-abscesses may be seen. Incipient
lesions of psoriasis may show minimal epidermal hyperplasia. In the eruptive form of psoriasis vulgaris
that follows b-hemolytic streptococcal infection, the epidermal hyperplasia is typically minimal and a
lymphocyte-dominant infiltrate with only few neutrophils may be observed. Probably the most useful and
distinctive diagnostic feature of psoriasis is the psoriatic capillary, the morphologic hallmarks of which
include the dilated capillary lying in direct apposition to basal layer keratinocytes of the epidermis.
Epidermal cell replication is markedly accelerated in active lesions of psoriasis. Keratinocyte
differentiation is also altered. Normally the suprabasilar epidermis expresses keratins K1-K10. In
psoriatic skin, keratins K1-K10 are replaced by the so-called hyperproliferative keratins, keratins K6 and
K16. In addition, involucrin, a major precursor protein of the cornified cell envelope normally found in
only in the very upper layers of the epidermis, is expressed prematurely in the lower superbasilar portion
of the epidermis.
There is an integral role for a T-lymphocyte mediated response in psoriasis. Oligoclonal expansion of
specific CD8+ve lymphocyte subsets, namely, those expressing V b 13.1 and V b 3 genes, has been
demonstrated. Psoriasis appears to be an example of Th1-mediated autoimmune disease, with Th cells
mediating the accumulation of the aforementioned CD8+ve oligoclones. As well, Th-lymphocytes produce
various cytokines including TNFa, a cytokine which may be involved in the formation of Munro microabscesses.
In addition, interferon also plays a role in the propagation of the psoriatic plaque; being over-expressed
by keratinocytes in psoriatic lesional skin. It has been hypothesized that decreased reponsiveness of
keratinocytes to IFNg may contribute to the hyperproliferation and altered differentiation of epidermal
cells in psoriasis. This protein has chemotatic as well as mitogenic properties. Interferon g also induces
the expression of intercellular adhesion molecules in keratinocytes and endothelial cells and mediates the
adhesion and trafficking of lymphocytes into the epidermis by binding to its ligand LFA-1. Among other
cytokines produced by the Th1 lymphocyte is IL8, which is a potent neutrophilic chemoattractant. As
psoriasis can follow streptococcal infection, a pathogenetic role for superantigens has been postulated;
superantigens induce a mitogenic response in large sub-populations of T-lymphocytes. Recent evidence has
suggested that there is a potential "psoriasis gene" located on chromosome 17Q. Attention has also been
focused on chromosome 1Q21. Genes clustered in this region are responsible for epidermal proliferation.
Psoriasis has also been associated with HLA-CW6, B13 and B17.
New Insights into the Pathophysiology of Psoriasis
Interactions between infiltrating T cells and keratinocytes via the secretion of the TH1 cytokines
interleukin (IL) 2 and interferon gamma (INF-gamma), the keratinocyte growth factor transforming growth
factor alpha (TGF-alpha) and the cytokines IL-6 and IL-8 are thought to be the predominant mechanisms
inducing skin lesions in psoriatic patients. Flow cytometric immunophenotyping of lymphocyte cultures
derived from psoriatic plaques reveals a CD4+ alpha beta receptor positive T lymphocyte population which
manifests a Th1 cytokine dominant milieu. The main Th1 cytokines are tumor necrosis factor beta,
interleukin 2, and interferon gamma while the main Th2cytokines are interleukin 4 and interleukin 10. In
psoriatic synovium, a Th1 dominant milieu along with the monokines tumor necrosis factor alpha and
interleukin 1 beta are at levels higher than the cytokine concentrations seen in the rheumatoid synovium.
Further support of a dominant Th1 cytokine milieu in the pathogenesis of psoriasis are the beneficial
effects of dimethyl and monomethyl fumaric acid on psoriatic skin lesions. This agent has been shown to
alter the cytokine milieu from a dominant Th1 profile to a TH2 dominant profile as revealed by reduced
levels of interferon gamma and interleukin 2 to a Th2 dominant profile revealed by high levels of
interleukin 10. In addition it suppresses the epidermal derived transforming growth factor alpha within
cultured keratinocytes. The presence of tissue eosinophilila in fumaric acid treated psoriatic plaques, the
classic light microscopic hallmark of a Th2 mediated immune response, provides a practical light microscopic
correlation of this altered cytokine profile. In one study monomethylfumaric acid greatly enhanced IL-4 and
IL-5 production without affecting IFN-gamma. When peripheral blood mononuclear cells were challenged with
Mycobacterium tuberculosis, an agent which typically induces Th1 recall responses with strong IFN-gamma
secretion, monomethylfumaric acid again appeared to induce high levels of IL-4 and IL-5 secretion while
IFN-gamma production was unaffected. There may be a critical role for IL12 in maintaining the Th1 response.
IL12 is a heterodimer cytokine which is important in the propagation of a Th1 immune response; this cytokine
is significantly elevated within the skin of psoriatic plaques compared to controls.
As psoriasis can follow streptococcal infection, a pathogenetic role for superantigens has been postulated;
superantigens induce a mitogenic response in large sub-populations of T-lymphocytes. Recent studies have
confirmed that psoriasis is likely an autoimmune disorder whereby the antigenic target is streptococcal
peptide which share homology with epidermal keratin. Recent papers have been published which support this
construct. Two studies showed that peripheral blood mononuclear cells in patients with psoriasis responded
with a Th1 dominant response to streptococcal M peptides which had sequence homology with epidermal keratin.
A similar response was not observed when peptides without sequence homology to epidermal keratin were used.
This excessive Th1 response was not seen in patients who had atopic eczema or were healthy controls.The
response was blunted during UVB treatment. An immunoperoxidase technique was used to look for
autoantibodies in autologous sera in skin sections obtained from lesions or from healthy areas of psoriatic
patients, before and after immunoadsorption with a Streptooccus pyogenes extract. The skin biopsies were
also analyzed with a pool of sera from mice immunized with the streptococcal extract. The investigators
found that all psoriatic patients had autoantibodies to antigens present in keratinocytes prior to
immunoadsorption with a Streptococcus pyogenes extract whereas healthy subjects did not. Immunoadsorption
of autologous sera removed the reactivity to antigens in skin lesions in all cases.
Further support of a role of the superantigens in the propagation of the psoriatic plaque was recently
demonstrated when staphylococcal enterotoxin B (SEB)-stimulated peripheral blood mononuclear cells from
psoriatic patients injected repeatedly under the grafted full-thickness involved psoriatic skin onto severe
combined immunodeficient (SCID) mice resulted in the persistence of a psoriasiform epidermis whereas those
mice with a single injection or injections of unstimulated peripheral blood mononuclear cells could not
maintain a hyperplastic epidermis. E-selectin expression interleukin-1 beta (IL-1 beta) and and interferon
gamma were only detected in those mice receiving continuous injections of stimulated peripheral blood
Psoriasis lesions are associated with increased numbers of cutaneous nerves. The pathogenetic basis of this
finding is unclear as is its significance regarding the pathogenesis of psoriasis. In psoriatic tissue the
number of keratinocytes per square millimeter of epidermis positive for nerve growth factor has been
demonstrated in non-lesional psoriatic skin rleative to normal skin and lichen planus. Nerve growth factor
is mitogenic to keratinocytes, activates T-lymphocytes and can induce migration of inflammatory cellular
infiltrates, histological features characteristic of psoriasis.
Some observers consider pustulosis palmoplantaris a localized form of pustular psoriasis. However a recent
study closely assessed the light microscopic appearance of these lesions, suggesting that it is a distinct
clinical pathological entity. Clinically there is a definite association with autoimmune thyroid disease
and smoking and gluten sensitive enteropathy. At a light microscopic level, inflammation preferentially
involves the acrosyringium and as well the infiltrate may contain eosinophils in addition to large numbers
of mast cells.
- Chang JCC, Smith LR, Froning KJ et al. Persistence of T-cell clones in psoriatic lesions. Arch
- Crowson AN. Superficial and deep perivascular dermatitis. In : Barnhill R, Crowson AN, Busam K,
Granter S ed's. Textbook of Dermatopathology. New York : McGraw-Hill Co, 1998:69-81.
- Crowson AN, Magro CM. Drug eruptions. In : Barnhill R, Crowson AN, Busam K, Granter S ed's. Textbook
of Dermatopathology. New York : McGraw-Hill Co,1998:257-270 de Jong R, Bezemer AC, Zomerdijk TP, van de
Pouw-Kraan T, Ottenhoff TH,
- Nibbering PH Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent
monomethylfumarate. Eur J Immunol 1996 Sep;26(9):2067-74
- Eriksson MO, Hagforsen E, Lundin IP, Michaelsson G. Palmoplantar pustulosis: a clinical and
immunohistological study. Br J Dermatol 1998 Mar;138(3):390-8
- Gillum PS, Golitz LE. Psoriasiform dermatitis. In : Barnhill R, Crowson AN, Busam K, Granter S ed's.
Textbook of Dermatopathology. New York : McGraw-Hill Co, 1998.55-68.
- Gottleib AB. Immunopathogenesis of psoriasis. Arch Dermatol 1997;133:781-2.
- Hawk JLM, Smith NP, Black MM.The photosensitivity disorders. In : Elder D, Elenitsas R, Jaworsky C,
Johnson B, Ed's. Lever's Histopathology of the skin, 8th Ed'n, Philadelphia: Lippincott-Raven,
- Horiuchi N, Aiba S, Sugawara S, et al. Peripheral blood lymphocytes from psoriatic patients are
hyporesponsive to --streptococcal superantigens. Br J Dermatol 1998;138:229-235.
- Horrocks C, Holder JE, Berth-Jones J, Camp RD. Antigen-independent expansion of T cells from psoriatic
skin lesions:phenotypic characterization and antigen reactivity.B r J Dermatol 1997 Sep;137(3):331-8.
- Perez-Lorenzo R, Zambrano-Zaragoza JF, Saul A, Jimenez-Zamudio L, Reyes-Maldonado E, Garcia-Latorre E
Autoantibodies to autologous skin in guttate and plaque forms of psoriasis and cross-reaction of skin
antigens with streptococcal antigens. Int J Dermatol 1998 Jul;37(7):524-31
- Ockenfels HM, Schultewolter T, Ockenfels G, Funk R, Goos M. The antipsoriatic agent dimethylfumarate
immunomodulates T-cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network. Br J
Dermatol 1998 Sep;139(3):390-5
- Raychaudhuri SP, Jiang WY, Farber EM. Psoriatic keratinocytes express high levels of nerve growth
factor. Acta Derm Venereol 1998 Mar;78(2):84-6
- Ritchlin C, Haas-Smith SA, Hicks D, Cappuccio J, Osterland CK, Looney RJ. Patterns of cytokine
production in psoriatic synovium. J Rheumatol 1998 Aug;25(8):1544-52
- Sigmundsdottir H, Sigurgeirsson B, Troye-Blomberg M, Good MF, Valdimarsson H, Jonsdottir I. Circulating
T cells of patients with active psoriasis respond to streptococcal M-peptides sharing sequences with human
epidermal keratins. Scand J Immunol 1997 Jun;45(6):688-97
- Toussaint S, Kamino H. Noninfectious erythematous, papular, and squamous diseases. In: Elder D,
Elenitsas R, Jaworsky C, Johnson B, Ed's. Lever's Histopathology of the skin, 8th Ed'n, Philadelphia:
- Valdimarsson H, Sigmundsdottir H, Jonsdottir I Is psoriasis induced by streptococcal superantigens and
maintained by M-protein-specific T cells that cross-react with keratin- Clin Exp Immunol 1997 Jan;107 Suppl
- Weedon D. Reactions to physical agents. In : Skin Pathology. Edinburgh : Churchill Livingstone.
- Weedon D. The psoriasiform reaction pattern. Skin Pathology. Edinburgh : Churchill Livingstone.
- Yamamoto T, Matsuuchi M, Katayama I, Nishioka K . Repeated subcutaneous injection of staphylococcal
enterotoxin B-stimulated lymphocytes retains epidermal thickness of psoriatic skin-graft onto severe
combined immunodeficient mice.J Dermatol Sci 1998 May;17(1):8-14
- Yawalkar N, Karlen S, Hunger R, Brand CU, Braathen LR. Expression of interleukin-12 is increased in
psoriatic skin. J Invest Dermatol 1998 Dec;111(6):1053-7